Is there a rise of prevalence for Molar Incisor Hypomineralization? A meta-analysis of published data

Since Molar Incisor Hypomineralization was first described as a pathologic entity, public perception often suggests a considerable rise in prevalence of the respective disease. Since there are still considerable doubts regarding the etiology and—accordingly—prevention of MIH and respective therapeutic approaches are difficult this question is of considerable clinical and public interest. Accordingly, a systematic literature search in accordance with the PRISMA guidelines for systematic reviews on Medline, Cochrane Database, EMBASE, LILACS, Web of Science, Google scholar, Scopus was performed to retrieve original articles reporting the prevalence of MIH as defined by the European Academy of Pediatric Dentistry (EAPD). From initially 2360 retrieved titles, 344 full texts were assessed for possible inclusion and finally 167 articles of mainly moderate to high quality and based on data of 46′613 individuals were included in the meta-analysis. All studies published before 2001 had to be excluded since it was not possible to align the findings with the EAPD classification. Studies varied considerably regarding cohort size (25 to 23′320, mean 1′235)) and age (5.6–19 y, mean 9.8 y). Over all studies, the weighted mean for the prevalence for MIH was 12.8% (95% CI 11.5%-14.1%) and no significant changes with respect to either publication year or birthyear were found. A sub-analysis of eleven studies reporting on the prevalence in different age groups, however, revealed strong evidence for an increasing prevalence between the years 1992 (3%) and 2013 (13%). Therefore, based on data from cross-sectional studies a possible rise in prevalence of MIH remains unclear. Future prospective large-scale studies under standardized examination conditions with an emphasis on examiner calibration are needed to gain better understanding in the evolution of the prevalence of MIH. Supplementary Information The online version contains supplementary material available at 10.1186/s12903-023-03637-0.


Introduction
While hypomineralization in the deciduous and permanent dentition have been found in human teeth 100′000 years of age [1] and have been studied scientifically since over a hundred years [2] a new focus and special clinical interest has been set on this form of developmental tooth disorder in the industrialized and post-industrialized world when caries turned out to be a highly controllable scourge for both deciduous and permanent teeth [3].In the late 90 s of the twentieth century hypomineralization in otherwise healthy first molars and incisors of the permanent dentition were described and -independently or as a consequence -observed more often [4].This finding gave rise to concern, and in 2001 the respective manifestation was defined as a new dental disease and was then called the molar-incisor-hypomineralization (MIH).Already in 2003 the European Academy of Pediatric Dentistry stated the pediatric dentists' awareness to this new dental disease's symptoms, which was then defined as a hypomineralization of at least one first molar of the permanent dentition, which is often also accompanied by hypomineralization of the central and lateral incisors [5].Since then, professional alertness towards MIH did not fade.Plenty of studies have been performed on etiology, epidemiology and different methods to treat MIH [6,7].While the exact etiology of MIH remains still unclear today's understanding based on the available evidence is, that MIH has a multifactorial etiology: Genetic reasons with codings on multiple genes seem to constitute only one of umpteen predisposing factors [8].Furthermore, MIH seems also to be associated with environmental risk factors, of which respiratory issues and infections, malnutrition, certain medication and vitamin D during childhood have been reported to have an effect [9][10][11][12].
Regarding the correct diagnosis for MIH, the special features and the typical localization of MIH lesions have to be carefully distinguished from other kinds of enamel hypomineralization (i.e., Turner teeth especially in case of incisors, initial carious lesions), hypomineralization (i.e., amelogenesis imperfecta) or other chemically induced disturbances during tooth development [13,14].The latter are often observed with a symmetrical pattern, while for the others careful clinical differential diagnosis (i.e., affection of all teeth in the case of amelogenesis imperfecta, localization of carious lesions in a dentition with active carious lesions) may lead to the definitive categorization.
For dental professionals, the treatment is often challenging because children affected by MIH are often less compliant due to frequently present tooth hypersensitivity [15,16].Furthermore, restorative treatment is technically challenging since it is still matter of discussion how deeply the altered tooth structure should be removed before restoration [17], and respective guidelines are subjected to constant changes [18,19].
Other than for experts only, MIH has gained a huge repercussion in media [20].Parents are concerned for their children's dental wellbeing and studies show that MIH can in fact affect the parents' quality of life [21].
Within the 20 years since the formulation of a generally accepted and well-established definition of MIH huge effort were taken to assess the prevalence of MIH.In fact, in the meantime, there is data based on a vast number of observational studies from literally nearly all parts of the world [22][23][24].With symposia specifically held for MIH, media pushing the issue and health care providers advertising specific products for the treatment of MIH (https:// www.aapd.org/ educa tion/ meeti ngs-calen dar-aapd/ inter natio nal-sympo sium-on-molar-hypom inera lisat ion-and-chalk yteeth/https:// europe.gc.dental/ sites/ europe.gc.dental/ files/ produ cts/ downl oads/ equia forte ht/ leafl et/ LFL_ Treat ment_ Solut ions_ for_ MIH_ de.pdf ) there is the perception that MIH has become more and more prevalent since the specific problem had been addressed for the first time in 2001.To the best of the authors' knowledge there has no systematical approach been made however to scientifically assess whether published data may substantiate the assumed fact of a rising prevalence.Accordingly, the focused question of this review was to assess, whether or not there is -based on the present data of epidemiologic studies -any robust indication for an increasing incidence of MIH.A special focus was set on the meta-analysis of studies reporting on subgroups of different age brackets and the question whether an increased prevalence in younger children was deductible.

Materials and methods
The review was registered on PROSPERO (CRD42021243950) and performed following the guidelines for Preferred Research Items for Systematic Reviews and Meta-Analysis (PRISMA) [25].
Literature search included observational and case-control-studies (control groups were assessed if not adapted to special predisposing factors of the respective cases) which provided prevalence data for MIH according to the definition of the EAPD [5], Weerheijm [4] or if a definition was given that corresponded exactly to the latter.
The electronic search was performed on Medline, Cochrane Database, EMBASE, LILACS, Web of Science, Google scholar, Scopus according to a search strategy adapted to the specific database, combining different search items related to Molar Incisor Hypomineralization and prevalence and study design (see Additional file 1 Table 1).
The inclusion criteria comprised observational (crossover or case control studies (only control group cohorts of the latter) reporting on the prevalence of MIH in populations which were not preselected (i.e., special exposition to environmental factors) and supposedly representative for the population.
MIH was accepted in terms of the MIH definition by EAPD 2003 [5] or Weerheijm [4] or DDE [26] with modifications which rendered an adaptation to the EAPD definition possible.It was planned to exclude all publications which would not clearly define hypomineralizations of the first molars which were not found to be due to dental fluorosis, enamel hypoplasia, or amelogenesis imperfecta.
No language restrictions were set.Exclusion criteria encompassed studies assessing specific cohorts of populations which were not rated representative for the whole population, i.e., populations with special medical background and diseases, or cohorts exposed to special environmental factors, or studies addressing one of the sexes only.Likewise, studies which did not report on a clinical method of diagnosis of MIH (i.e., photos, scans, etc.) were excluded.
Duplicates from the electronic search were removed.In a first step titles and abstracts were screened for possible inclusion by two independent reviewers.Studies were kept in the screening process if at least one reviewer included it for full text assessment.Subsequently, full texts were assessed for possible inclusion.In order to avoid overestimation of cohorts that were assessed several times, only data of one study were considered.In this regard, the publication with the most comprehensive data was included to the review, or -as a secondary criterium when data was equally comprehensive, the most recent study was considered.
From studies accepted for inclusion and from reviews regarding the topic, reference lists were scrutinized for further studies potentially meeting the inclusion criteria, and potential hits were likewise considered for inclusion.
In a final step data from all full texts which finally fit to the inclusion criteria were extracted and recorded addressing the following items: Author/year, region of clinical examination, clinical assessment period, sampling environment (i.e., dental clinic, school room,…), study type (cross-sectional or case-control), MIH definition, equipment used for the clinical examination (i.e., air drying, headlight, etc.), cohort characteristics/population (age and gender proportions, provenience), cohort size, prevalence of MIH (and which teeth were reported), treatment needs, funding sources and data regarding the quality assessment of the studies (Table 1).

Quality assessment
With the aim to assess the risk of potential bias of the individual studies, a modified GRADE scale for risk assessment was used, involving the parameters representativeness of the cohort, sample size calculation, calibration of the examiners and case definition.If no high risk of bias for any of these parameters were detected, the study was rated as high quality, with one parameter with a high risk of bias the study was rated moderate and with more than one parameter with high risk of bias the study was rated as low quality.

Statistical methods
The outcome of interest was the prevalence of MIH reported across studies.The summary estimate for MIH across studies was obtained with a random effects metaanalysis model, based on restricted maximum likelihood estimation.For each meta-analysis, the estimated heterogeneity variance parameter τ 2 was reported together with the measure of heterogeneity I 2 .In graphical representations, the prevalences reported across studies were shown in relation to assessment period and birth period.
In order to show forest plots, subgroups of studies including different birth cohorts were displayed.Further, there were some studies that reported an age-dependent prevalence of MIH, with different follow-up times across studies.The reported prevalences are shown in a visualization, indicating which prevalence resulted from the individual cohort.In this context, a generalized linear regression model was fitted in order to evaluate in an exploratory approach, whether there was evidence for an increasing prevalence over time.For this, the repeated measurements across studies were addressed with a random intercept, but the size of the included studies was not accounted for in a meta-analysis framework.Statistical calculations were performed with the programming language R version 4.1.1(2021-08-10) in a fully scripted approach using dynamic reporting.

Results
The electronic search revealed 2′369 titles and abstracts.Of these, 344 full-texts were considered for possible inclusion.After removing studies reporting on the same cohort, studies which did not provide suitable data presentation for the prevalence of MIH as defined in the method chapter and studies which assessed cohorts obviously non-representative for the general population, data of 167 distinct studies were finally included into the meta-analysis.
None of the publications before 2001 were found to allow for a proper definition of hypomineralizations of the first molars, or rather a clear delimitation from dental fluorosis, enamel hypoplasia, or amelogenesis imperfecta.Accordingly, all these studies were excluded from the meta-analysis.
The entire study selection process is illustrated in Fig. 1.

Quality assessment
While most of the studies included to the meta-analysis were of medium quality (148), the studies covered the whole range from high (58) over moderate (70) to low (31) quality.The most frequent reason for limited quality was missing sample size calculation (199) followed by missing inter-examiner reliability (134) (Additional file 1 Table 2).Studies included to the review were published after 2001 but several examinations had taken place considerably before.Data from 46′613 individuals had been considered in the present review.The assessed cohorts in the different studies varied from 25 to 23′320 children with a mean cohort size of 1′235 infants across studies.The assessed population varied in age from 5.6 to 19 years of age and were at a weighted mean age of 9.8 years old.The weighed mean proportion of boys, where reported, was 51% across studies, ranging from 28 to 100% while in 42 of the included studies, no information on children's sex was reported.
Figure 2a indicates the prevalences of MIH related to the year of publication, while Fig. 2b shows the prevalences related to the birthyears of the study participants, by subtracting the cohort's mean age from the year of examination.The prevalences were loess-smoothed, and the curve is shown with 95% confidence intervals.
Across all studies, the prevalence of MIH ranged between 0.48% and 46.6% resulting in a summary estimate across studies based on a random-effects metaanalysis model of 12.8% (95% CI 11.5%-14.1%),with τ 2 being 0.56, and I 2 being equal to 98.5%.To address the question whether a different classification scheme would affect the estimation of the prevalence, the classification type was added as a moderator in a random effects model.The corresponding p-value was 0.17, indicating that there was no evidence for a moderating effect of the classification scheme.
To show the prevalence of MIH in forest plots, subgroups of birth year ranges were defined with the cutoff values for the birth years being A) before 1997, B) between 1997-2003 and C) from 2003 on (Fig. 3a-c).
Prevalence across studies with repeated follow-up assessments.
The analysis on the data of studies which reported repeatedly prevalences in groups at different ages was based on 11 studies (see Table 1a [27-30, 32-37, 143]).The respective data is based on a total of 50`611 (range 404-23320) patients with an aged from 6 to 15y from Western Europe and Asia.In all studies, MIH was diagnosed based on ethe EAPD criteria or according to Weerheijm.Regarding the proportion of males and females there was no relevant deviation.Generally, MIH prevalence ranged from 2.9 to 19.3 in the respective studies.It shows a continuous rise in prevalence for MIH from the earliest examination in 1992 to the most recent available in 2011 (Fig. 4).The corresponding p-value for a linear time trend showed strong evidence for an increasing prevalence.Based on the merged data on the respective studies the prevalence of MIH show a rise from 6 to 14% from the years 2000 to 2010.A sub-analysis of the prevalence over time shows considerable differences for the prevalence of MIH between the regions previously described by Schwendicke et al. [22].While for most areas there are few studies and they are therefore not eligible for a sound analysis, the areas "North African and Middle East" and "Central Latin America" show a rise in prevalence while the areas "Tropical Latin America" and "High-income Asia Pacific" show a respective decline (see Additional file 1 Fig. 1).

Discussion
Molar incisor hypomineralization has become an important topic in pediatric dentistry within the last 20 years [19,182].Since the perceived prevalence is continuously rising and the impact for affected children and their families are considerable [21] plenty of epidemiologic studies have been performed all over the world [22], but so far, no systematic approach has been investigating whether there is actually any indication for any rise in prevalence from scientific literature.Merging data on weighted means of prevalence for MIH failed in either of the performed calculations to indicate a rise over time: Neither for the raw data presented in 167 studies nor after adjusting the data to the actual age of the populations in which the studies had been performed revealed an enhanced prevalence.Ideally, however, the question whether there is a raise in the prevalence of MIH would be answered by studies assessing children of the same age group after a considerable time span of several years under standardized and wellcalibrated conditions.Therefore, in a separate analysis on data from studies with age-specific prevalences for the assessed children and adolescents was performed.The results draw a different conclusion: Based on this specific data from 11 high quality studies (see Supplemental Table 2), in fact, a considerable rise based on studies from Europe, Africa, Asia, South America and Oceania in the prevalence of MIH becomes evident.Important to highlight, however, that this result is not based on a meta-analysis model due to the complexity of the data structure with multiple reportings across single studies.For this reason, the results will need confirmation in prospective studies.
With an average of 12.8% the mean value from the studies considered for the present meta-analysis are slightly lower than those of two recent reviews with 13.1% and 14.2% [22,183].Nevertheless, the results are in the same range, and small differences may be attributed to the later publication date or recent publications which have not been considered in the previous reviews.Given that both, age distribution and proportion of males and females did not differ considerably to the previous reviews, renders the latter options for a potential bias rather unlikely and seems to confirm the relevance of more recent data.
The results of the present systematic review should however be considered with care: Many studies and reviews estimating the prevalence of MIH have been highlighting the limits of the individual reports (due to a considerable bias level as assessed also for the present study): The cohorts themselves might not always exactly depict the population in which the examinations were performed, the definition of MIH might slightly vary while data on the inter-examinators agreement have not always been reported.Furthermore, sample size calculations, a measure which aims for avoiding statistical type II errors, were not performed in all of the studies included into the present review (see Supplemental Table 2, quality assessment) [184].Then it is important to highlight, that data on prevalence show a vast range from 0.48% and 46.6% within the different studies [185], a strong indicator for the fact that merged data is based on a highly heterogeneous set of data.Generally, merged analysis of data from cohort studies of all different areas of the world bear several immanent risks like different operators and settings, and published changes for the prevalence of MIH in distinct populations or single nations might remain unperceived [54,138].
On the other hand, the results of this review are based on a comparatively high number of studies: With 167 studies on data of a total of 46′613 patients the results are based on a quite solid base and stands out from most comparative studies in dentistry.
Hypomineralization on first molars of the permanent dentition is not a new finding for sure.Several studies examining prehistoric dentitions show enamel demineralization with the typical features of MIH-affected teeth, namely an increasing mineralization from the enameldentine junction towards the tooth surface [186][187][188].Furthermore, there are plenty of examinations which were performed in the late last century.Though they assess hypomineralizations on a standardized and highly scientific level, a good deal of the respective data could not be used in the present meta-analysis due to the fact that the addressed hypomineralizations had not been specified exactly before 2001 [4], and MIH as an entity has not been defined before 2003 [5].Accordingly, the greatest part of 59 studies published from 1930 to 2002 had to be excluded, since a valid adaptation of the findings to the definition of MIH was not possible in these studies: Mostly, either the exact location on a permanent molar or a sufficient demarcation towards defects of similar appearance but of different origin like enamel altered by fluorosis, hypoplasia, Turner teeth or discoloration due to tetracyclines [13,14] was not possible.However, as a lucky matter of fact several examinations which had been performed before 2001 and the definition of MIH were published considerably later, then considering the definition of MIH which had been published recently before.Luckily, the new definition of MIH was quickly spread and adapted on then-published studies, what helped to find comparable data and, therefore, considerable evidence.
The fact that the prevalence of MIH might indeed rise by time is an important puzzle piece in MIH research since quantification of global and regional burden of MIH and the awareness of respective trends and changes in the prevalence is highly relevant for decision makers in the healthcare sector and health care providers [22].
Data on the prevalence of MIH merged in the metaanalyses showed a considerable range.The respective heterogeneity might be to many different reasons: While there might be different sources of bias like different levels of specificity and sensitivity of the operators, partially attributable to the examination settings in which they performed their examinations (see Table 1), the simple fact that all over the world different ethnicities were assessed [22] over a considerable time frame will have contributed to variations in the prevalence data.
With a range from 5.6 to 19 years, there was a considerably large heterogeneity for the age of the examined patients.While some studies assessed patient cohorts at a defined age, others involved children of mixed ages, while other studies assessed the prevalence of MIH in several defined age groups in follow-up appointments (Table 1a).Prevalence of MIH, however, has been reported be agedependent with a higher proportion in children younger than 10 years of age [183].In order to standardize examinations and respective results, optimal time points (5y for hypomineralised second primary molars and 8y for MIH)  [27-30, 32-37, 143] have been suggested [189].Regarding the inclusion criteria is should be highlighted, that the decision to include data from both, cross-sectional studies and from control cohorts of case-control studies generally bear a higher risk of Berkson's bias, the latter arising due to testing a subpopulation rather than the general population [190].This potential risk has been largely double-checked in the present study since the selection bias was assessed in the quality assessment.Thereby however, no substantial inferior quality for the controls cohorts form case-control studies could be determined.
The present review merges data from studies of different quality.The high proportion of low-rated studies might be seen as a limitation.However, low quality was already rated if more than on parameter was considered to have a high risk for a bias, thereby not rendering the study data unreliable, but highlighting the possible source of bias.

Conclusion
Merged data from cross-sectional studies do not indicate a rise in worldwide's prevalence of MIH.However, studies on age-specifical assessment show a rise from 6 to 14% in the years from 2000 to 2010 for the prevalence of MIH.
Further age-specific re-analysis of existing data on one side and future studies, which assess age-dependent prevalence of MIH on a high-quality level might unearth more knowledge about the dynamic of MIH prevalence than further unspecific reports on just mean prevalences.

Fig. 1 Fig. 2 a
Fig. 1 PRISMA flow diagram for the literature search

Fig. 4
Fig. 4 Prevalences of MIH in studies reporting separately on the prevalence of MIH for different ages.Each black dot indicates the prevalence of an individual study.Grey lines connect data from the same study population.The continuous black line shows the loess-smoothed prevalence across all study cohorts, the dashed lines indicate 95% confidence limits[27-30, 32-37, 143]

Table 1
Summary of the included studies.a) studies reporting prevalences at follow-up assessments for different age groups b) studies reporting general prevalence over the entire cohort

Table 1
(continued) Legend Classification: 1 -MIH classification according to the European Academy of Pediatric Dentistry (EAPD) or Weerheijm 2003 and 2 -according to the DDEclassification